Story of exitance of polymorphism dates back to the year 1812 when Napoleon Bonaparte army wore highly decorated and shiny buttons on the uniform. It was observed that these shining buttons of tin made in summers changed to dirty gray in winters. This change of the color of buttons from shining white to dirty gray at that time was considered by soldiers as God’s wrath. The scientific reason for crumbling of buttons can be attributed to polymorphic transition of Tin. In fact, β-form of tin is white and stable at 18°C while the α-form is gray and stable below this temperature. This change being the act of nature never got attention of the patent seekers and no patent protection was sought for different polymorphic forms of the Tin. However, this phenomenon of polymorphic transformation was found to be exhibited by a number of other inorganic, biological and pharmaceutical compounds. Curiously, polymorphism gained importance in the areas of chemical/drug molecules research where full characterization of materials is essential in determining their specific use, in pharmaceutical, pigment, agrochemical, explosive or fine chemical industry. In 1995 an antiretroviral drug for HIV infections and AIDS, (Norvir®) by Abbott Laboratories suffered a setback due to changes in its dissolution profile that forced its withdrawal from the market in 1998. It was later found that drug ritonavir exits in different polymorphic forms at high temperature which resulted in changing the bioavailability of the drug. Similarly, atorvastatin patents on polymorphs appeared in public debates when Pfizer introduced polymorphs of a block buster drug atorvastatin, (Lipitor®) in 1996. Pfizer in fact obtained patent for novel polymorphs of Atorvastatin (form-I, -II, -IV,). Form-I atorvastatin was the found to be most stable and effective form. This strategy of polymorphic patenting allowed Pfizer to extend market exclusivity of Atorvastatin by six additional years. Taking this as a cue many pharmaceutical companies now prefer to file polymorph patent in a separate application. Polymorph patents on Rifaximin and Sitagliptin are recent addition in this race.
Evergreening of patents
It is generally essential that the medicines are stable against humidity, temperature, light, and the like over a long period of time and also to have stability in the formulation step. It is preferred that most stable crystalline form of the medicinal entity is used. Under such technical circumstances, most of the inventors make extensive and intensive investigations about the prospective drug candidate before such molecule hit the commercial market. In certain cases, the mixture of crystalline form of the drug molecule is introduced in the market and later on patents its alpha, beta or gamma forms are additionally obtained. This practice in the terminology of generic drug manufactures is also called as evergreening of a patent. This approach was criticized by generic manufacturers as it delayed the entry of the generic version of the patented drug even after expiry of its patent term of 20 years .
Polymorphs and drug discovery
Polymorphism is now a widespread term, with its acceptance by the pharmaceutical industry from its regulatory and patentability point of view. In the initial years the study of polymorphs was limited to check their physical existence after crystallization. Later on, within the polymorphism landscape, the focus of research shifted to look for the presence of mixtures of crystalline phases and their reproducibility and purity. Further study on different crystalline forms of the medicinal molecules /new chemical entities lead to finding comparable and surprising results such as better therapeutic efficacy. For example, alpha forms of many drugs are found to be better than beta forms or their mixture. For instance, Out of the α-form crystal and β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino] ethyl ] acetanilide the α-form crystal does not exhibit hygroscopicity and has stability such that it can be used as a medicine for diabetes remedy and is useful for mass synthesis in the industrial production. However, the β-form crystal does not relatively exhibit hygroscopicity and it is useful as a production intermediate of the α-form crystal. (EP1440969A1).
Patentability Hitch
If the patentability of the polymorphs poses enigmatic and diverse view within the corridors of the IP offices, it raised debatable issues on its patent eligibility amongst the inventors seeking patent or those opposing its grant. Polymorphs of the medicinal entities exiting or otherwise remain the area of inquisit research in the search for better medicinal product with enhanced efficacy, stability, solubility, and shelf live. However, the patentability of polymeric compounds is subjected to invalidity in all most all the disputes relating to contested polymorph patents. Many developing countries and least developed countries introduced specific exclusions for different forms of known compound in their patent law For instance, section 3(d) of the Indian Patent Act 1970 as amended in 2005 clearly states that “the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance” is not patentable or even the “mere discovery of any new property or new use for a known substance” is kept out of list of patent eligibility in India. And for purpose these exclusion “salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy”.
Concept of therapeutic efficacy
The concept of efficacy as stated in explanation under section 3(d) was considered by a judgment of the Division Bench of the Madras High Court, in Novartis AG v. Union of India 2007 (4) MLJ 1153. The court held that:
“in sum and substance what the amended section with the Explanation prescribes is the test to decide whether the discovery is an invention or not is that the Patent applicant should show the discovery has resulted in the enhancement of the known efficacy of that substance and if the discovery is nothing other than the derivative of a known substance, then, it must be shown that the properties in the derivatives differ significantly with regard to efficacy. As we stated earlier, due to the advanced technology in all fields of science, it is possible to show by giving necessary comparative details based on such science that the discovery of a new form a of known substance had resulted in the enhancement of the known efficacy of the original substance and the derivative so derived will not be the same substance, since the properties of the derivatives differ significantly with regard to efficacy.”
Accordingly, it is understood that polymorphs of known or patented drug molecule depicting same efficacy will not find favour with of the Indian patent office for grant of a patent. Supreme court in Novartis case (Novartis Ag vs Union Of India & Ors on 1 April, 2013) clarified that the ‘efficacy’ referred in the explanation section 3(d) means ‘therapeutic efficacy’. Therefore, changes in patent eligibility criteria introduced in 2005 are significant as these changes introduced the concept of the need for the discovery of a new form of a known substance or a derivative, which is deemed to be a substance unless it differs significantly in properties with regard to its known efficacy. This decision left many drug molecules innovators to believe that patents on polymorphs with same efficacy will not be allowed by the Indian patent office.
Position of polymorph patents in EPO
It is not that patents on polymorphs are freely available in other patent offices like EPO. The naturally exiting polymeric forms of a compound may not qualify for patent for the simple reason that such forms can be deemed within the disclosed prior art. However, if new process is developed to obtain a new polymorph patent may be permitted if it involves inventive step. Experimental data is crucial for polymorph applications. The EPO manual suggests that a specific polymorph could be novel as compared to an amorphous form or a crystalline form of the compound in general. However, the applicant must give supporting data to establish an inventive step of the claimed polymorph. In T777/08 EPO Board of appeal discussed the patent eligibility of the polymorph and consider inventive step determinant standards at the EPO. The Board held that
“[I]n the absence of any technical prejudice and in the absence of any unexpected property, the mere provision of a crystalline form of a known pharmaceutically active compound cannot be regarded as involving an inventive step.”
“When starting from the amorphous form of a pharmaceutically active compound as the closest prior art, the skilled person would have a clear expectation that a crystalline form thereof would provide a solution to the problem of providing a product having improved filterability and drying characteristics. The arbitrary selection of a specific polymorph from a group of equally suitable candidates cannot be viewed as involving an inventive step.”
In more recent cases EPO emphasizes the need to show an unexpected property linked to the claimed Polymorph. For example, in T0041/17, a polymorph of sorafenib tosylate that is stable under mechanical stress was found to be obvious because it is the most thermodynamically stable polymorph. Board observed that screening and isolation of the most thermodynamically stable polymorph was generally encouraged by the prior art, and the most thermodynamically stable polymorph was expected to be stable under mechanical stress. Similarly, in T1894/15, board observed that a polymorph of tigecycline that is stable towards epimerisation was found to be obvious because the prior art taught that crystalline forms of tetracyclines (tigecycline being a tetracycline) are more chemically stable than the respective amorphous form and, for tigecycline, chemical stability encompasses stability towards epimerisation.
Polymorphs with unexpected properties Patentable
In case the applicant is able to prove that the claimed polymorph possessed an unexpected property and comparative data is available, especially to distinguish between different polymorphs, patents are allowed in number of cases by EPO. Commonly allowed cases are where polymorphic stability (stability against interconversion between polymorphs) is one property that can support an inventive step. EPO opposition Board considered this as technical effect and patents were allowed in T2114/13, T1555/12 and T1326/18. In T0325/16, two polymorphs having different degrees of polymorphic stability were found to be inventive compared to a disclosure of a general crystalline form of the compound. In some cases, physical stability argument worked to support an inventive step. In T1684/16, for example a polymorph of bosutinib monohydrate was found to be inventive, because the polymorph had improved stability in terms of appearance, purity, water content and crystallinity compared to both the solid form and another crystalline form. In T0699/05, a novel process of using a laser to induce nucleation of a polymorph was found inventive.
Patentability of polymorphs in US
In Grünenthal Gmbh v. Alkem Labs. Ltd. the ground of obviousness was raised to invalidate US 7,994,364 in an appeal case before the United States Federal Circuit (Fed. Cir. Mar. 28, 2019). The polymorphic compound in question was tapentadol hydrochloride (tapentadol) directed to Form A of tapentadol hydrochloride. Federal Circuit affirmed a district court finding that a patent was not invalid for obviousness. The Court acknowledge the fact that tapentadol was a polymorphic compound that was unknown in the art at the time and Byrn alone provided insufficient guidance as to what particular solvents, temperatures, agitation rates, etc., were likely to result in Form A. However, Federal court categorically stated, that “[o]ur decision today does not rule out the possibility that polymorph patents could be found obvious.” If it is found lacking inventive step patent is mostly denied.
Diametrically opposite view on patentability of Polymorphs
There are two diametrically opposite sides of the patentability of the polymorphs. One side believed that polymorphism is natural phenomenon and polymorphs are not invented or created. They are discovered as a routine during experimentation relating to drug formulations. Other equally tenable view is that the search for new polymorphs of the existing or new drug molecules with surprising properties in relation to a particular drug molecule is a tedious and expensive exercise. How different polymorphs can be used in different ways of formulation during drug development depend on its surprising characteristics. Recent trends show that finding a best polymorph is an essential and major component of new drug development. Unsurprisingly, only small number of new chemical entities gets approval for marketing annually and majority of patent applications are based on improved polymers of the existing drug molecules or process of their manufacture. All these research efforts are centered on improving the drug efficacy, safety and quality of treatment of the known drugs. This is also called second generation of patents and they are often branded as an effort to evergreen the exiting patent after its expiry. Patentability of such variation at times faces though opposition from the patent office or the opponents. It is known that new polymorph and process of its manufacture is a patentable subject matter. Ranitidine (polymorph type II), Paroxetine and Cefdinir are most successful examples of second-generation patent comprising polymorphs with enhanced efficacy, stability, bioavailability, and improved shelf life. The requirements of regulatory filing for new drug application (NDA) or abbreviated new drug application (ANDA) are stringent in US and other countries including India. This requires drug molecule innovators to carry out extensive polymorphic studies before a product can be brought to market.
Polymorphs Patentability: Position in India
Unsurprisingly, patented polymorphs of drug molecules are now increasingly subjected to obviousness test challenge in almost all the invalidity suits in India and elsewhere. Speaking on the patentability requirement under the Patents Act 1970 as amended in 2005, Delhi high court in F. Hoffmann-La Roche Ltd. And Anr. vs Cipla Limited (148 (2008) DLT 598, MIPR 2008 (2) 35) [Tarseva / Erlotinib case] observed that
“The Parliament consciously enacted the standard of non- obviousness as a condition for patentability; it also excluded some matter, i.e., derivatives of substances which are known to exist, unless they differ in properties, significantly, in the known efficacy. Thus, it has to be concluded that the test of non-obviousness of an invention and discovery of existence of significant enhancement in the known efficacy of a substance are pre-requisites of patentability. In other words, even if non-obviousness of an invention in the pharmaceutical or Chemical industry are established, the applicant should also prove that if the invention claimed is the derivative of a known substance, it does not fall within the excepted category, in the Explanation to Section 3(d) as it comprehends a discovery of significant enhancement in known efficacy of such known substance.”
In Indian context filing of the experimental data is crucial to win over a patent grant. Indian examines insists on submission/disclosure of experimental data in all application claiming polymorphs of known compounds. Though Indian law is sufficient to guide examiner to consider the grant of polymorphs they are likely to influenced by the precedent in US and EPO to deny patent if no evidence to support its claimed efficacy / properties is disclosed/submitted during examination. Curiously speaking European Board in T0256/13, refused a claim to a polymorph in absence of data to support the claimed property. Losing a patent for lack of data can be cured if the applicant files an application with evidence for the polymorph’s properties rather than taking risk to file application at an early stage of drug development.
Cautionary remarks
Twin requirements for patent eligibility such as novelty and non-obviousness are also considered for grant of patents on polymorphs. Chemically speaking, a new crystal form of a drug molecules is novel. If such crystal forms cannot be predicted a priori they are also not obvious. We have seen that many new crystal forms are patentable and have been patented, especially in the pharmaceutical field in India and other jurisdictions. Crystal forms/polymorphs of other chemical compounds have also been patented. The high visibility of patent litigations on the polymorph patents on drugs in particular, in Indian and other jurisdiction, may caution the patent seekers to prepare well before filing the patent applications claiming polymorphs. Otherwise, you are more likely to get entangled in contentious litigation involving purely technical and scientific issues as happened in the litigations relating to ranitidine hydrochloride, cefadroxil, terazosin hydrochloride, and aspartame etc. A polymorph made in a routine manner and not having an unexpected property is unlikely to be consider as inventive by examiner. Therefore, seeking patent for polymorphs obtained through isolation and screening in routine manner is not worthwhile as it may fail inventive step test in all IPO jurisdictions including India. However, a new process for obtaining a polymorph is more likely to support an inventive step. In India and even in EPO, identification and proving an unexpected property of the new polymorph is essential to establish the sound grounds of its patent eligibility. It will take some more time to clearly understand how the Indian patent examiner applies patent law and precedents to relook on the patentability of intended polymorphs with increased bioavailability, safety, and efficacy. Nonetheless, Section 3d of the Indian Patent Act 1970 allows polymorphic patents involving technological advancements. Comparative data on unexpected propertied of polymorph is crucial and without its disclosure in the patent specification, a polymorph patent application is more likely fail in India. In view of the tapentadol cases discussed above patents covering polymorphic compounds may become more difficult to invalidate in US and to some extent in India on the ground of obviousness if prior art fail to disclose which specific variables should be altered, or to what extent they should be altered, to obtain a polymorph. Patents directed to a polymorph can be an effective way to obtain second or third generation protection for a successful drug molecule. An expert advice would be useful if you are planning to obtain patents on polymorphs in India and elsewhere.
Article by DPS Parmar